PURPOSE: GTI-2040, a 20-mer phosphorothioate oligonucleotide, was designed to hybridize to the mRNA sequence of human ribonucleotide reductase R2. GTI-2040 has been shown to inhibit human cancer cell proliferation by downregulation of R2 expression in vitro and to significantly inhibit tumor growth in xenograft models of human cancer in mice. As part of the safety evaluation for human clinical trials, the toxicity and toxicokinetics of GTI-2040 were determined in Sprague-Dawley rats and rhesus monkeys. METHODS: GTI-2040 was administered to rats at 2, 10, and 50 mg/kg/day by bolus intravenous injection every second day for 21 days with a 21-day recovery. In monkeys, an acute study was performed with single, escalating doses of GTI-2040 ranging from 10 to 80 mg/kg given as a 24-h continuous intravenous infusion. As well, a 21-day, continuous intravenous infusion study with GTI-2040 was conducted in monkeys at 2, 10, and 50 mg/kg/day, with a 3-week recovery. Blood sampling was done to measure GTI-2040 plasma concentrations, metabolites, and pharmacokinetic parameters, and tissues were collected to assess the distribution of GTI-2040 and/or metabolites. RESULTS: The toxicities of GTI-2040 in both rats and monkeys were typical for the phosphorothioate oligonucleotide class of compounds. In monkeys, there was a dose-related increase in GTI-2040 plasma levels with concomitant increase in complement activation and prolongation of activated partial thromboplastin time. In both rats and monkeys, the tissues having the highest concentrations of GTI-2040 (kidney, liver, spleen) had the largest dose-related toxic effects. Adverse effects were diminished or absent in the recovery animals. CONCLUSIONS: GTI-2040 was well tolerated when infused over 24 h at doses up to 80 mg/kg in monkeys. In rats and monkeys, GTI-2040 was reasonably well tolerated and showed reversible toxicities when administered at doses up to 50 mg/kg/day for 21 days. The no observed adverse effect dose level for GTI-2040 in both animal species was 2 mg/kg/day. There were no apparent sequence-specific effects related to the interaction of GTI-2040 with the R2 component of the mRNA expressing ribonucleotide reductase.
PURPOSE:GTI-2040, a 20-mer phosphorothioate oligonucleotide, was designed to hybridize to the mRNA sequence of human ribonucleotide reductase R2. GTI-2040 has been shown to inhibit humancancer cell proliferation by downregulation of R2 expression in vitro and to significantly inhibit tumor growth in xenograft models of humancancer in mice. As part of the safety evaluation for human clinical trials, the toxicity and toxicokinetics of GTI-2040 were determined in Sprague-Dawley rats and rhesus monkeys. METHODS:GTI-2040 was administered to rats at 2, 10, and 50 mg/kg/day by bolus intravenous injection every second day for 21 days with a 21-day recovery. In monkeys, an acute study was performed with single, escalating doses of GTI-2040 ranging from 10 to 80 mg/kg given as a 24-h continuous intravenous infusion. As well, a 21-day, continuous intravenous infusion study with GTI-2040 was conducted in monkeys at 2, 10, and 50 mg/kg/day, with a 3-week recovery. Blood sampling was done to measure GTI-2040 plasma concentrations, metabolites, and pharmacokinetic parameters, and tissues were collected to assess the distribution of GTI-2040 and/or metabolites. RESULTS: The toxicities of GTI-2040 in both rats and monkeys were typical for the phosphorothioate oligonucleotide class of compounds. In monkeys, there was a dose-related increase in GTI-2040 plasma levels with concomitant increase in complement activation and prolongation of activated partial thromboplastin time. In both rats and monkeys, the tissues having the highest concentrations of GTI-2040 (kidney, liver, spleen) had the largest dose-related toxic effects. Adverse effects were diminished or absent in the recovery animals. CONCLUSIONS:GTI-2040 was well tolerated when infused over 24 h at doses up to 80 mg/kg in monkeys. In rats and monkeys, GTI-2040 was reasonably well tolerated and showed reversible toxicities when administered at doses up to 50 mg/kg/day for 21 days. The no observed adverse effect dose level for GTI-2040 in both animal species was 2 mg/kg/day. There were no apparent sequence-specific effects related to the interaction of GTI-2040 with the R2 component of the mRNA expressing ribonucleotide reductase.
Authors: Mark H Kirschbaum; Paul Frankel; Timothy W Synold; Zhiliang Xie; Yun Yen; Leslie Popplewell; Robert Chen; Omar Aljitawi; Joseph M Tuscano; Kenneth K Chan; Edward M Newman Journal: Leuk Lymphoma Date: 2016-02-19
Authors: Keith T Gagnon; Hannah M Pendergraff; Glen F Deleavey; Eric E Swayze; Pierre Potier; John Randolph; Eric B Roesch; Jyoti Chattopadhyaya; Masad J Damha; C Frank Bennett; Christophe Montaillier; Marc Lemaitre; David R Corey Journal: Biochemistry Date: 2010-11-08 Impact factor: 3.162
Authors: Maja M Janas; Carole E Harbison; Victoria K Perry; Brenda Carito; Jessica E Sutherland; Akshay K Vaishnaw; Natalie D Keirstead; Garvin Warner Journal: Toxicol Pathol Date: 2018-08-23 Impact factor: 1.902